Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia–retinoic acid receptor-α (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-γ (IFN-γ). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wolff, J.A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 (1990).
Stevenson, F.K. et al. Idiotypic DNA vaccines against B-cell lymphoma. Immunol. Rev. 145, 211–228 (1995).
Syrengelas, A.D., Chen, T.T. & Levy, R. DNA immunization induces protective immunity against B-cell lymphoma. Nat. Med. 2, 1038–1041 (1996).
King, C.A. et al. DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. Nat. Med. 4, 1281–1286 (1998).
Spellerberg, M.B. et al. DNA vaccines against lymphoma: promotion of anti-idiotypic antibody responses induced by single chain Fv genes by fusion to tetanus toxin fragment C. J. Immunol. 159, 1885–1892 (1997).
Brown, D. et al. A PMLRARα transgene initiates murine acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA 94, 2551–2556 (1997).
Lallemand-Breitenbach, V. et al. Retinoic acid and arsenic synergize to eradicate leukemic cells in a mouse model of acute promyelocytic leukemia. J. Exp. Med. 189, 1043–52 (1999).
Kogan, S.C., Hong, S.H., Shultz, D.B., Privalsky, M.L. & Bishop, J.M. Leukemia initiated by PMLRARα: the PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable. Blood 95, 1541–1550 (2000).
Bogen, B. Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma. Eur. J. Immunol. 26, 2671–2679 (1996).
Rice, J., Elliott, T., Buchan, S. & Stevenson, F.K. DNA fusion vaccine designed to induce cytotoxic T cell responses against defined peptide motifs: implications for cancer vaccines. J. Immunol. 167, 1558–1565 (2001).
Chen, S.A. et al. Induction of antitumor immunity with combination of HER2/neu DNA vaccine and interleukin 2 gene-modified tumor vaccine. Clin. Cancer Res. 6, 4381–4388 (2000).
Westervelt, P. et al. Adaptive immunity cooperates with liposomal all-trans-retinoic acid (ATRA) to facilitate long-term molecular remissions in mice with acute promyelocytic leukemia. Proc. Natl. Acad. Sci. USA 99, 9468–9473 (2002).
Dermime, S. et al. Lack of T-cell-mediated recognition of the fusion region of the pml/RAR-α hybrid protein by lymphocytes of acute promyelocytic leukemia patients. Clin. Cancer Res. 2, 593–600 (1996).
Gambacorti-Passerini, C. et al. Human CD4 lymphocytes specifically recognize a peptide representing the fusion region of the hybrid protein pml/RAR α present in acute promyelocytic leukemia cells. Blood 81, 1369–1375 (1993).
Finn, O.J. & Forni, G. Prophylactic cancer vaccines. Curr. Opin. Immunol. 14, 172–177 (2002).
Forni, G., Lollini, P.L., Musiani, P. & Colombo, M.P. Immunoprevention of cancer: is the time ripe? Cancer Res. 60, 2571–2575 (2000).
Hu, J. et al. An evaluation of the potential to use tumor-associated antigens as targets for antitumor T cell therapy using transgenic mice expressing a retroviral tumor antigen in normal lymphoid tissues. J. Exp. Med. 177, 1681–1690 (1993).
Lufkin, T. et al. High postnatal lethality and testis degeneration in retinoic acid receptor α mutant mice. Proc. Natl. Acad. Sci. USA 90, 7225–7229 (1993).
Mark, M. et al. A genetic dissection of the retinoid signalling pathway in the mouse. Proc. Nutr. Soc. 58, 609–613 (1999).
Dresser, D.W. Adjuvanticity of vitamin A. Nature 217, 527–529 (1968).
Zhu, J. et al. Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins. Proc. Natl. Acad. Sci. USA 96, 14807–14812 (1999).
Stephensen, C.B. et al. Vitamin A enhances in vitro Th2 development via retinoid X receptor pathway. J. Immunol. 168, 4495–4503 (2002).
McConkey, S.J. et al. Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat. Med. 9, 729–735 (2003).
Krieg, A.M. CpG motifs: the active ingredient in bacterial extracts? Nat. Med. 9, 831–835 (2003).
Cassinat, B. et al. Quantitation of minimal residual disease in acute promyelocytic leukemia patients with t(15;17) translocation using real-time RT-PCR. Leukemia 14, 324–328 (2000).
Sambrook, J., Fritsch, E.F. & Maniatis, T. Plasmid vectors. in Molecular Cloning. A Laboratory Manual, 1.33–1.52 (Cold Spring Harbor Laboratory Press, New York, 1989).
de The, H. et al. The PML-RAR α fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66, 675–684 (1991).
Delva, L. et al. Physical and functional interactions between cellular retinoic acid binding protein II and the retinoic acid-dependent nuclear complex. Mol. Cell. Biol. 19, 7158–7167 (1999).
Parrado, A. et al. Retinoic acid receptor α1 variants, RARα1δB and RARα1δBC, define a new class of nuclear receptor isoforms. Nucleic Acids Res. 29, 4901–4908 (2001).
Lust, J.A., Kumar, V., Burton, R.C., Bartlett, S.P. & Bennett, M. Heterogeneity of natural killer cells in the mouse. J. Exp. Med. 154, 306–317 (1981).
We thank P. Chambon and C. Rochette-Egly for the RAR-α antibodies and GST-RAR-α plasmid, H. de Thé for the full-length PML-RARA construct and N. Westwood for help in preparing the manuscript. Financial support was provided by the Leukaemia Research Fund of Great Britain (R.A.P. and F.S.), the Welsh Bone Marrow Transplant Research Fund of Great Britain (R.A.P.), the Fulbright Commission (R.A.P.), the French Fondation pour la Recherche Medicale (R.A.P.), the French Association de Recherche contre le Cancer (C.C. and P.R.), the French Ligue Nationale contre le Cancer (R.A.P. and C.C.), the Fondation Saint-Louis (J.L.), the Fondation de France (M.H.S.), the Kay Kendall Leukaemia Fund (R.A.P. and S.M.), Eli Lilly (R.A.P. and T.H.P.), INSERM (R.A.P., M.P., H.T., D.C. and C.C.) and the National Institutes of Health (J.M.B.).
The authors declare no competing financial interests.
About this article
Cite this article
Padua, R., Larghero, J., Robin, M. et al. PML-RARA–targeted DNA vaccine induces protective immunity in a mouse model of leukemia. Nat Med 9, 1413–1417 (2003). https://doi.org/10.1038/nm949
The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy
Frontiers in Oncology (2019)
Nature Reviews Cancer (2018)
Leukemia & Lymphoma (2018)
Arsenic Trioxide Enhances the NK Cell Cytotoxicity Against Acute Promyelocytic Leukemia While Simultaneously Inhibiting Its Bio-Genesis
Frontiers in Immunology (2018)
Cancer Cell (2017)